Evidence for the role of CD74 in innate immunity, arthritis, and the action of migration inhibitory factor

Recent studies have identified CD74, the cell surface form of the class II-associated invariant chain, as a binding site for the cytokine macrophage migration inhibitory factor (MIF). MIF is implicated in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, but a functional relationship between MIF and CD74 in inflammation has not been demonstrated. We used CD74^-/- mice to examine the role of this molecule in cellular and in vivo inflammatory responses, using innate immune response-dependent models to avoid confounding by the role of MHC Ii in adaptive immunity.

MIF has a demonstrated role in macrophage responses to endotoxin. LPS induced IL-1, IL-6, TNF and MIF release from WT bone-marrow macrophages. Bone-marrow macrophages lacking CD74 released significantly lower amounts of IL-1 and IL-6, but no difference in TNF release was evident. LPS-induced MIF release by WT and CD74^-/- bone-marrow macrophages was also similar. Murine K/BxN serum-transfer arthritis is MIF dependent [1], and also requires the induction of IL-1. Compared with WT mice, arthritis severity (clinical score) was significantly lower in mice lacking CD74 (P < 0.05). These data imply but do not demonstrate a role of CD74 in MIF-dependent inflammatory responses. To confirm the role of CD74 in responses to MIF in vivo, we examined a recently described action of MIF – the induction of leukocyte trafficking [2]. rhMIF was injected into mouse cremaster tissue and leukocyte–endothelial interactions examined using intravital microscopy. MIF induced leukocyte adhesion and emigration in vivo in WT mice. In CD74^-/- mice, in contrast, this response could not be elucidated.

These data demonstrate for the first time the role of CD74 in innate immune responses and inflammatory arthritis, and demonstrate for the first time in vivo the requirement for CD74 for the action of MIF. A functional role for CD74 in MIF responses in inflammation is strongly supported.